Thanks

  • Felicia Magpantay, Matthieu Domenech de Cellès, Carles Bretó, Jennie Lavine, Daihai He
  • Ed Ionides, Pej Rohani, Mercedes Pascual
  • US National Institutes of Health
  • US National Science Foundation
  • US NIH/DHS Research and Policy for Infectious Disease Dynamics Program
  • US National Center for Ecological Analysis and Synthesis & the “Inference for Mechanistic Models” Working Group

Models have many uses

  • Organizing data
  • Developing theoretical principles
  • Exploring hypotheticals
  • Guiding policy
  • Explaining observed patterns

Mechanistic models as scientific instruments

In seeking to understand biological phenomena, models are tools for looking at the data.

They focus attention on the discrepancies between our hypotheses and reality.

How to quantify these discrepancies?

The key principle of statistics is that we must model the error.

Mechanistic models as scientific instruments

  • In seeking to infer causal mechanism in intact biological systems, dynamics are especially informative.
  • Hypotheses about causal mechanisms can often readily be formalized as dynamical systems models.
  • The problems of inference
    • How can we estimate unknown parameters?
    • How can we decide among competing models?
    • How can we extract maximum information from time series data?
  • When do we know when we need a better model vs better data?

Sources of error

The key principle is that we must model the error.

  • Measurement error
    • Error
    • Finite precision
  • Process noise
    • Environmental trends and fluctuations
    • Unmodeled heterogeneities
    • Model misspecification
    • Unmodeled variables

Overview

  1. Markov models
  2. Examples: cholera and pertussis
  3. Partially observed Markov processes
  4. Plug and play inference methods
  5. Plug and play methods in practice
  6. Conclusions and recommendations

Compartmental models and stochastic differential equations

Compartmental models and stochastic differential equations

Compartmental models and stochastic differential equations

Compartmental models and stochastic differential equations

Compartmental models and stochastic differential equations

Compartmental models and stochastic differential equations

Compartmental models and stochastic differential equations

\[ \begin{aligned} dN_{XY}&=\lambda\,X\,dt+\sigma_{XY}(X)\,dW_1(t)\\ dN_{X\emptyset}&=\mu\,X\,dt+\sigma_{X\emptyset}(X)\,dW_2(t)\\ \end{aligned} \]

\[dW_1,dW_2\;\stackrel{i.i.d}{\sim}\;\mathrm{Normal}(0,\sqrt{dt})\]

Compartmental models and stochastic differential equations

\[ \begin{aligned} dX&=B\,dt-dN_{XY}-dN_{X\emptyset}\\ &=B\,dt-(\lambda+\mu)\,X\,dt\\ &\qquad-\sigma_{XY}(X)\,dW_1(t)-\sigma_{X\emptyset}(X)\,dW_2(t)\\ dY&=dN_{XY}\\ &=\lambda\,X\,dt+\sigma_{XY}(X)\,dW_1(t)\\ \end{aligned} \]

Overview

  1. Markov models
  2. Examples: cholera and pertussis
  3. Partially observed Markov processes
  4. Plug and play inference methods
  5. Plug and play methods in practice
  6. Conclusions and recommendations

Endemic cholera

Endemic cholera

Endemic cholera

Endemic cholera

Endemic cholera

Endemic cholera

Scientific questions

  1. Relative importance of human-human vs environmental transmission
  2. Duration of infection-induced immunity
  3. Roles of seasonal and multiennial climate drivers
    • complex seasonality
    • multiennial cycles
  4. Importance of bacteriophage in environment

Transmission models

Transmission models

Transmission models

Transmission models

Transmission models

Transmission models

Transmission models

Transmission models

  • nonlinear
  • stochastic
  • nonstationary
  • extrinsically driven

Mechanistic models

  • How well do each of the models explain the data?
  • What insights can we gain into the system’s dynamic self-regulation?

Note that the structure of the models corresponds to the questions of scientific interest, without regard to issues of mathematical tractability.

Scientific questions

  1. Relative importance of human-human vs environmental transmission
  2. Duration of infection-induced immunity
  3. Roles of seasonal and multiennial climate drivers
    • complex seasonality
    • multiennial cycles
  4. Importance of bacteriophage in environment

The ongoing pertussis resurgence


(Lavine, King, and Bjørnstad 2011)

The ongoing pertussis resurgence


(Domenech de Cellès, Magpantay, King, and Rohani 2016)

Scientific question

Why the resurgence?

  • Changes in vaccine efficacy
  • Vaccine-driven pathogen evolution
  • Increased circulation of congeneric pathogens
  • Asymptomatic transmission
  • Loss of natural immune boosting
  • Increased surveillance sensitivity

Key unknowns:

  • durability of vaccine-induced immunity
  • relative efficacy of natural- and vaccine-derived immunity

Models of vaccine failure

\[\lambda(t) = \frac{\beta(t)\,(I_1+\theta\,I_2)+\bar{\beta}\,\iota}{N}\]

Post-vaccination infections are observed at a reduced rate, \(\eta\).

(Magpantay, Domenech de Cellès, Rohani, and King 2016)

Models of vaccine failure

  • Can we estimate the nature and durability of vaccine-induced protection?
  • Which models explain the data adequately?
  • Questions of parameter estimation and model selection

(Magpantay et al. 2016)

Pertussis resurgence in progress

(Domenech de Cellès, Magpantay, King, and Rohani 2018)

Pertussis resurgence in progress

(Domenech de Cellès et al. 2018)

Pertussis resurgence in progress

(Domenech de Cellès et al. 2018)

Pertussis resurgence in progress

(Domenech de Cellès et al. 2018)

Pertussis resurgence in progress

(Domenech de Cellès et al. 2018)

Pertussis resurgence in progress

(Domenech de Cellès et al. 2018)

Pertussis in Massachusetts

(Domenech de Cellès et al. 2018)

Age-structured models of vaccine failure

(Domenech de Cellès et al. 2018)

Time-varying covariates

(Domenech de Cellès et al. 2018)

Time-varying covariates

(Domenech de Cellès et al. 2018)

Age-structured contact network

(Domenech de Cellès et al. 2018; Rohani, Zhong, and King 2010)

Age-structured contact network

(Fumanelli, Ajelli, Manfredi, Vespignani, and Merler 2012; Mossong et al. 2008)

Inference about vaccine failure

  • Can we estimate the nature and durability of vaccine-induced protection?
  • Which models explain the data adequately?
  • Questions of parameter estimation and model selection

(Domenech de Cellès et al. 2018)

Overview

  1. Markov models
  2. Examples: cholera and pertussis
  3. Partially observed Markov processes
  4. Plug and play inference methods
  5. Plug and play methods in practice
  6. Conclusions and recommendations

Partially observed Markov processes


(King, Nguyen, and Ionides 2016)

Partially observed Markov processes


(King et al. 2016)

Partially observed Markov processes


(King et al. 2016)

Partially observed Markov processes


(King et al. 2016)

Partially observed Markov processes

(King et al. 2016)

Partially observed Markov processes

  • observation times: \(t_1 < t_2 < \dots < t_N\)
  • data: \(y_{t_n}^*\)
  • unobserved Markov state process: \(X_t\)
  • measurement process: \(Y_t\)
  • process model (Markov state transition density): \(f_n(X_{t_n}|X_{t_{n-1}},\theta)\)
  • measurement model: \(g_n(Y_{t_n}|X_{t_{n-1}},\theta)\)
  • initial state distribution \(f_0(X_{t_0},\theta)\)

(King et al. 2016)

Central problem

The full joint density is:

\[f_{X,Y}(x,y;\theta) = f_0(x_0;\theta)\,\prod_{n=1}^N\!f_{n}(x_n|x_{n-1};\theta)\,g_{n}(y_n|x_n;\theta).\]

The likelihood function is the marginal density for \(Y\), evaluated at the data:

\[ \begin{split} \mathcal{L}(\theta)&=f_{Y}(y^*_1,\dots,y^*_n;\theta)\\ &=\int f_{X,Y}(x_0,\dots,x_N,y^*_1,\dots,y^*N;\theta)\, dx_1\cdots dx_n. \end{split} \]

Perils of mechanistic models

  • computing the likelihood requires integrating over \(X_t\)
    for all \(t\)
  • traditional solution—be very clever:
    • simplify the model to make it statistically tractable
    • devise and tune an inference algorithm (e.g., MCMC sampler) specifically to the model
  • but: are we testing just our hypothesis or the statistical method also?
  • it is perilous to invest too much time in one model
    • the Pygmalion problem
    • an antidote: the method of multiple working hypotheses

The “plug and play” property

Definition: an algorithm has the plug-and-play property if it has no need to evaluate the process model density \(f(X_t|X_{t-1})\).

Plug-and-play methods access the process model only via simulation.

This puts minimal restrictions on the form of the models that can be entertained.

(He, Ionides, and King 2010; King et al. 2016)

Overview

  1. Markov models
  2. Examples: cholera and pertussis
  3. Partially observed Markov processes
  4. Plug and play inference methods
  5. Plug and play methods in practice
  6. Conclusions and recommendations

Plug and play inference methods

  • Feature-based methods
    • Approximate Bayesian computation (ABC)
    • Nonlinear forecasting (NLF)
    • Attractor-reconstruction based methods
    • Probe matching
    • Synthetic likelihood
  • Full-information methods (likelihood based)
    • Sequential Monte Carlo (the particle filter)
    • Particle Markov chain Monte Carlo
    • Iterated filtering

Available in the pomp software package (King et al. 2016): [https://kingaa.github.io/pomp/]

Synthetic likelihood

Given parameters \(\theta\in\Theta\) and data \(y^*\in\mathcal{Y}\)

  • Select probes (summary statistics), \(\mathbb{S}:\mathcal{Y}\to\mathbb{R}^d\)
  • Compute observed probes, \(s^* = \mathbb{S}(y^*)\)
  • Simulate \(J\) datasets \(y_j\) and compute simulated probes \(s_j=\mathbb{S}(y_j)\)
  • Using sample mean, \(\mu = \langle s_j \rangle\), and variance, \(\Sigma = \langle (s_j-\mu)\,(s_j-\mu)^T \rangle\), compute the synthetic log likelihood \[\ell_{\mathbb{S}}(\theta) = -\tfrac{1}{2}\,(s^*-\mu)^{T}{\Sigma}^{-1}(s^*-\mu)-\tfrac{1}{2}\,\log((2\pi)^d|\Sigma|)\]
  • E.g., maximize \(\ell_{\mathbb{S}}\) over \(\Theta\)

(Fasiolo, Pya, and Wood 2014; Wood 2010)

The particle filter

  • Given \(\theta\) and \(y^*\), initialize particle swarm by drawing \(X^F_{t_0,j}\sim f_0(\cdot|\theta)\), \(j=1,\dots,J\)
  • For \(n = 1,\dots,N\),
    • Simulate for prediction: \(X^P_{t_{n},j}\sim f_k(\cdot|X^F_{t_{n-1},j},\theta)\)
    • Evaluate weights: \(w_{n,j} = g(y^*_{t_{n}}|X^P_{t_{n},j},\theta)\)
    • Perform weighted resample of \(\{X^P_{t_n,j}\}_{j=1}^J\) to obtain \(\{X^F_{t_n,j}\}_{j=1}^J\)
    • Estimate conditional log likelihood: \(\ell_{n}(\theta) = \log\mathrm{Prob}[y^*_{t_n}|y^*_{t_1},\dots,y^*_{t_{n-1}}] = \log\tfrac{1}{J}\sum_j\!w_{n,j}\)
  • Unbiased estimate of the log likelihood: \(\ell(\theta) = \sum_n\,\ell_n(\theta)\)

(Arulampalam, Maskell, Gordon, and Clapp 2002)

Particle Markov chain Monte Carlo

  • Given \(\theta_0\), compute \(\ell(\theta_0)\) using the PF
  • For \(m>0\), draw \(\theta^P_m\sim q(\cdot|\theta_{m-1})\)
  • Compute \(\ell(\theta^P_m)\) using the PF
  • Generate \(U\sim\mathrm{Uniform}(0,1)\)
  • Set \(\theta_m=\begin{cases}\theta^P_m, &\text{if } U<\frac{f_\Theta(\theta^P_m)\exp(\ell(\theta^P_m))}{f_\Theta(\theta_{m-1})\exp(\ell(\theta_{m-1}))},\\ \theta_{m-1},&\text{otherwise.}\end{cases}\)
  • Repeat until the Markov chain converges

Because the particle filter gives as unbiased, though noisy, estimate of the likelihood, this MCMC converges to the correct target distribution.

(Andrieu, Doucet, and Holenstein 2010)

Iterated filtering

  • main problem with particle filter: particle depletion
  • basic idea of iterated filtering:
  • replace fixed parameters by parameters that execute a random walk, e.g., \[\theta \mapsto \theta_n \sim \mathrm{Normal}(\theta_{n-1},\sigma)\]
  • this combats particle depletion by introducing variability
  • also permits local exploration of the likelihood surface
  • take \(\sigma\to 0\) iteratively
  • analogies with simulated annealing

(Ionides, Bretó, and King 2006; Ionides, Nguyen, Atchadé, Stoev, and King 2015; King et al. 2016)

Iterated filtering

  • Choose starting point \(\theta_0\) and random-walk perturbations \(\sigma_{m}\), \(m=0,1,2,\dots\).
  • Initialize particle swarm by drawing \(\theta^F_{j,0} \sim \mathrm{Normal}(\theta_0,\sigma_0)\)
  • For \(m>0\), run PF to obtain \(\{\theta^F_{j,m}\}_{j=1}^J\)
  • Repeat unto convergence
  • The \(\theta^F\) converge to the maximum likelihood estimate of \(\theta\)

(Ionides et al. 2015)

Overview

  1. Markov models
  2. Examples: cholera and pertussis
  3. Partially observed Markov processes
  4. Plug and play inference methods
  5. Plug and play methods in practice
  6. Conclusions and recommendations

Common model comparison criteria

  • The best model agrees with already published results
  • The best model is the one that I can estimate before my thesis is due
  • The best model is the one that best agrees with my preconceptions
  • The best model is the one that makes my supervisor the happiest
  • An identifiable model is better than a non-identifiable model
  • The best model is the one with the narrowest confidence intervals

Valid model comparison criteria

  • How well does the model fit the data?
    • How does the likelihood compare to benchmark values?
    • Does the model fit well? (fitting best \(\ne\) fitting well )
  • How does the model explain the data?
    • What aspects of the data are explained?
    • What aspects are ascribed to noise?
  • Model adequacy
    • Are the data consistent with the model’s assumptions?
    • If the model were correct, how plausible are the data?

Valid model comparison criteria

  • Predictive power
    • Can the model make accurate out-of-sample predictions?
  • What predictions to parameter estimates make about the results of independent studies?
  • Fertility
    • Does the model make testable predictions?

Endemic cholera


(King, Ionides, Pascual, and Bouma 2008)

Likelihood profile

(King et al. 2008)

Profile trace plots

(King et al. 2008)

Endemic cholera

Endemic cholera


Is it necessary that all infected individuals be equally infectious?
(King et al. 2008)

Asymptomatic infections

case fatality: \(0.34\pm 0.2\)
duration of immunity \(1.5 \pm 0.7~\text{yr}\)
(King et al. 2008)

Pertussis and vaccine failure

\[\lambda(t) = \frac{\beta(t)\,(I_1+\theta\,I_2)+\bar{\beta}\,\iota}{N}\]

Post-vaccination infections are observed at a reduced rate, \(\eta\).

(Magpantay et al. 2016)

Pertussis and vaccine failure

Interpretation: in vaccinated hosts, infections are mild to asymptomatic, yet equally infectious

(Magpantay et al. 2016)

Limits to information

Flat profiles indicate lack of information in the data relative to the question

It is extremely useful to know when you cannot know.

(Magpantay et al. 2016)

Exploiting the age structure

  • relative transmissibility 0.99 [0.40–1.00]
  • relative observability 0.39 [0.19–1.00]
  • high detection rates in adolescents and in adults: 24% [10–66%]
  • despite effectiveness, eradication via routine immunization alone is not possible
    (Domenech de Cellès et al. 2018)

Overview

  1. Markov models
  2. Examples: cholera and pertussis
  3. Partially observed Markov processes
  4. Plug and play inference methods
  5. Plug and play methods in practice
  6. Conclusions and recommendations

Relative merits

  • SL throws away information, but gains robustness
  • Many choices are possible for SL probes, with consequences for inference
  • IF converges much faster than PMCMC
  • Frequentist vs Bayesian inference styles
  • Smoothed state trajectories can be computed by PMCMC
  • Probes can be used for post hoc checks of model adequacy

Recommendation: an integrated approach

  • Use IF, profile likelihood, and profile trace plots to identify heights in the likelihood surface.
  • Use PMCMC to obtain posterior densities and smoothed state trajectories if desired.
  • Use independent parameter estimates to diagnose model misspecification.
  • Use probes to ascertain model adequacy and diagnose model misspecification.

Conclusions

  • It is essential to model the error, including both process noise and measurement error.
  • Plug-and-play inference methods facilitate scientific investigation.
  • Effective, statistically efficient plug-and-play inference methods are available.
  • There is an abiding need for further methodological development of such methods to improve computational efficiency and accommodate new data types.

References

Andrieu C, Doucet A, Holenstein R (2010). “Particle Markov Chain Monte Carlo Methods.” Journal of the Royal Statistical Society, Series B, 72(3), 269–342. https://doi.org/10.1111/j.1467-9868.2009.00736.x.

Arulampalam MS, Maskell S, Gordon N, Clapp T (2002). “A Tutorial on Particle Filters for Online Nonlinear, Non-Gaussian Bayesian Tracking.” IEEE Trans Signal Process, 50, 174–188. https://doi.org/10.1109/78.978374.

Domenech de Cellès M, Magpantay FMG, King AA, Rohani P (2016). “The Pertussis Enigma: Reconciling Epidemiology, Immunology, and Evolution.” Proceedings of the Royal Society of London. Series B,

Domenech de Cellès M, Magpantay FMG, King AA, Rohani P (2018). “The Impact of Past Vaccination Coverage and Immunity on Pertussis Resurgence.” Sci Transl Med, 10(434), eaaj1748. https://doi.org/10.1126/scitranslmed.aaj1748.

Fasiolo M, Pya N, Wood S (2014). “Statistical Inference for Highly Non-Linear Dynamical Models in Ecology and Epidemiology.” http://arxiv.org/abs/1411.4564

Fumanelli L, Ajelli M, Manfredi P, Vespignani A, Merler S (2012). “Inferring the Structure of Social Contacts from Demographic Data in the Analysis of Infectious Diseases Spread.” PLoS Computational Biology, 8(9), e1002673. https://doi.org/10.1371/journal.pcbi.1002673.

He D, Ionides EL, King AA (2010). “Plug-and-Play Inference for Disease Dynamics: Measles in Large and Small Populations as a Case Study.” J R Soc Interface, 7, 271–283. https://doi.org/10.1098/rsif.2009.0151.

Ionides EL, Bretó C, King AA (2006). “Inference for Nonlinear Dynamical Systems.” Proc Natl Acad Sci, 103(49), 18438–18443. https://doi.org/10.1073/pnas.0603181103.

Ionides EL, Nguyen D, Atchadé Y, Stoev S, King AA (2015). “Inference for Dynamic and Latent Variable Models via Iterated, Perturbed Bayes Maps.” Proc Natl Acad Sci, 112(3), 719–724. https://doi.org/10.1073/pnas.1410597112.

King AA, Ionides EL, Pascual M, Bouma MJ (2008). “Inapparent Infections and Cholera Dynamics.” Nature, 454(7206), 877–880. https://doi.org/10.1038/nature07084.

King AA, Nguyen D, Ionides EL (2016). “Statistical Inference for Partially Observed Markov Processes via the R Package Pomp.” J Stat Softw, 69(12), 1–43. https://doi.org/10.18637/jss.v069.i12.

Lavine JS, King AA, Bjørnstad ON (2011). “Natural Immune Boosting in Pertussis Dynamics and the Potential for Long-Term Vaccine Failure.” Proceedings of the National Academy of Sciences of the U.S.A., 108(17), 7259–7264. https://doi.org/10.1073/pnas.1014394108.

Magpantay FMG, Domenech de Cellès M, Rohani P, King AA (2016). “Pertussis Immunity and Epidemiology: Mode and Duration of Vaccine-Induced Immunity.” Parasitology, 143, 835–849. https://doi.org/10.1017/S0031182015000979.

Mossong J, Hens N, Jit M, Beutels P, Auranen K, Mikolajczyk R, Massari M, Salmaso S, Tomba GS, Wallinga J, et al. (2008). “Social Contacts and Mixing Patterns Relevant to the Spread of Infectious Diseases.” PLoS Medicine, 5(3), e74. https://doi.org/10.1371/journal.pmed.0050074.

Rohani P, Zhong X, King AA (2010). “Contact Network Structure Explains the Changing Epidemiology of Pertussis.” Science, 330(6006), 982–985. https://doi.org/10.1126/science.1194134.

Wood SN (2010). “Statistical Inference for Noisy Nonlinear Ecological Dynamic Systems.” Nature, 466, 1102–1104. https://doi.org/10.1038/nature09319.